Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.
World J Gastroenterol. Nov 14, 2026; 32(42): 121690
Published online Nov 14, 2026. doi: 10.3748/wjg.121690
Surufatinib achieves radiosensitivity in cholangiocarcinoma by suppressing GINS4 expression to induce Ca2+/cAMP signaling activation
Ai Huang, Yang Cao, Bin Li, Jun Xiao, Su-Dong Zhan, Ning-Yu Wang, Xiang-Ping Mei, Si-Zhe Zhao, Jun Han, Yong Xiao, Lin-Fang Wang, Hong Ma
Ai Huang, Ning-Yu Wang, Xiang-Ping Mei, Si-Zhe Zhao, Jun Han, Hong Ma, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
Ai Huang, Ning-Yu Wang, Xiang-Ping Mei, Si-Zhe Zhao, Jun Han, Hong Ma, Hubei Key Laboratory of Precision Radiation Oncology, Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, Hubei Province, China
Ai Huang, Ning-Yu Wang, Xiang-Ping Mei, Si-Zhe Zhao, Jun Han, Hong Ma, Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
Yang Cao, Jun Xiao, Su-Dong Zhan, Yong Xiao, Lin-Fang Wang, Department of Gastrointestinal Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
Bin Li, Department of Anesthesiology, General Hospital of the Central Theater Command, Wuhan 430060, Hubei Province, China
Co-first authors: Ai Huang and Yang Cao.
Co-corresponding authors: Lin-Fang Wang and Hong Ma.
Author contributions: Huang A and Cao Y contributed equally to this study and they are co-first authors. Huang A, Cao Y, Li B, and Xiao J designed the study; Zhan SD, Wang NY, Mei XP, and Zhao SZ performed the experiments; Han J, Wang LF, Xiao Y, and Ma H analyzed the data; Wang LF and Ma H contributed equally to this work and serve as co-corresponding authors. and all authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
AI contribution statement: AI tools (specifically ChatGPT) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Supported by China Health & Medical Development Foundation, No. chmdf2024-xrzx04-07; and Chinese Society of Clinical Oncology, No. Y-SY201901-0014.
Institutional animal care and use committee statement: This study was approved by the Medical Ethics Committee of Shanghai Gene Chem (Approval No. GSZE0346553), and the study followed the ethical guidelines of the Declaration of Helsinki.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Corresponding author: Hong Ma, Chief Physician, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan 430022, Hubei Province, China.
wudajianzhu2004@163.com
Received: April 1, 2026
Revised: May 15, 2026
Accepted: September 8, 2026
Published online: November 14, 2026
Processing time: 174 Days and 19.5 Hours
BACKGROUND
The tyrosine kinase inhibitor surufatinib demonstrates antitumor activity in biliary tract cancer (BTC). Previous evidence suggests that it exhibits a potential radiosensitizing effect when combined with radiotherapy (RT).
AIM
To assess surufatinib’s potential to enhance radiosensitivity and to explore the associated mechanisms.
METHODS
BTC cell lines NOZ and TFK-1 were utilized. Cell proliferation inhibition, radiosensitizing effects, and induction of DNA damage and apoptosis by surufatinib were detected using colony formation, immunofluorescence, and flow cytometry analyses. A cholangiocarcinoma tumor-bearing mouse model was established to validate the in vivo effects. High-throughput sequencing, Gene Set Enrichment Analysis (GSEA), genetic interventions and western blotting were performed to identify key genes and signaling pathways associated with surufatinib treatment and radiosensitization.
RESULTS
Surufatinib significantly inhibited proliferation and was associated with enhanced radiosensitivity in BTC cell lines. Combined with RT, surufatinib increased radiation-induced DNA damage and apoptosis. In vivo, surufatinib markedly inhibited angiogenesis and was associated with a radiosensitizing effect. Transcriptome sequencing identified GINS4 as a differentially expressed gene, with its expression correlating with poor prognosis. Knockdown of GINS4 inhibited tumor proliferation and enhanced the therapeutic efficacy of surufatinib combined with RT. Conversely, GINS4 overexpression promoted tumor proliferation, which was suppressed by surufatinib combined with RT. GSEA analyses suggested that GINS4 is closely associated with the Ca2+/cAMP signaling pathway. Surufatinib combined with RT was associated with suppressed GINS4 expression and concomitant activation of Ca2+/cAMP signaling in association with increased apoptosis.
CONCLUSION
Our study suggests that surufatinib is associated with radiosensitization in cholangiocarcinoma, potentially through inhibition of GINS4 expression and activation of the Ca2+/cAMP signaling pathway, leading to increased radiation-induced cellular damage and apoptosis. Further mechanistic studies are needed to establish causality.
Core Tip: Surufatinib has been approved for the treatment of advanced cholangiocarcinoma. Our clinical trial demonstrates that surufatinib exerts prominent radiosensitizing effects. Its synergistic anti-tumor activity with radiotherapy is mainly achieved by suppressing the expression of GINS4, a critical proliferation-related gene, while simultaneously triggering the activation of Ca2+/cAMP signal cascades. Such molecular changes amplify radiation-triggered DNA injury, aggravate irreversible cellular damage, and ultimately facilitate robust apoptotic death of tumor cells upon radiation exposure. Our study provides more therapeutic options for clinical treatment.
